Involvement of extracellular signal-regulated kinase module in HIV-mediated CD4 signals controlling activation of nuclear factor-kappa B and AP-1 transcription factors.
Although the molecular mechanisms by which the HIV-1 triggers either T cell activation, anergy, or apoptosis remain poorly understood, it is well established that the interaction of HIV-1 envelope glycoproteins with cell surface CD4 delivers signals to the target cell, resulting in activation of transcription factors such as NF-kappa B and AP-1. In this study, we report the first evidence indicating that kinases MEK-1 (MAP kinase/Erk kinase) and ERK-1 (extracellular signal-regulated kinase) act as intermediates in the cascade of events that regulate NF-kappa B and AP-1 activation upon HIV-1 binding to cell surface CD4. We found that CEM cells transfected with dominant negative forms of MEK-1 or ERK-1 do not display NF-kappa B activation after HIV-1 binding to CD4. In contrast, NF-kappa B activation was observed in these cells after PMA stimulation. Although the different cell lines studied expressed similar amounts of CD4 and p56(lck), HIV-1 replication and HIV-1-induced apoptosis were slightly delayed in cells expressing dominant negative forms of MEK-1 or ERK-1 compared with parental CEM cells and cells expressing a constitutively active mutant form of MEK-1 or wild-type ERK-1. In light of recently published data, we propose that a positive signal initiated following oligomerization of CD4 by the virus is likely to involve a recruitment of active forms of p56(lck), Raf-1, MEK-1, and ERK-1, before AP-1 and NF-kappa B activation.
Briant
L
L
Centre de Recherches de Biochimie Macromoléculaire, Laboratoire d'Immunologie des Infections Rétrovirales, Institut de Biologie, Montpellier, France.
Robert-Hebmann
V
V
Sivan
V
V
Brunet
A
A
Pouysségur
J
J
Devaux
C
C
D017209:Apoptosis / Q000276:immunology; D001692:Biological Transport / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000939:Epitopes / Q000276:immunology; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D006801:Humans; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000276:immunology
D015704:CD4 Antigens; D000939:Epitopes; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases